Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairments and cognitive deterioration. Aging and family history are the major risk factors for AD. Furthermore, increasing evidence indicates that astrocytes and microglia are implicated in the pathogenesis of AD. The major genetic risk factor for late onset AD is the APOE genotype. The inheritance of the APOE4 allele increased the risk of AD. APOE is secreted by astrocytes and stimulates A? neuronal production and reduced clearance. Furthermore, genome-wide association studies (GWAS) have identified polymorphisms in genes enriched in microglia (e.g. SORL1, CR1, CD2AP, CD33, TREM2) and astrocytes (e.g. CLU and ABCA7) that increase the risk of developing AD. Recent advances in stem cell technology have allowed the reprogramming of primary cells from human subjects into induced pluripotent stem cells (iPSCs) and their differentiation in neurons, astrocytes and microglia. However, conventional 2D culture systems fail to recapitulate the diversity and maturation of multiple cell types and their interaction under physiological and pathological conditions. To overcome these weaknesses we have developed a novel bioengineered model of iPSC-derived neural tissue. Our silk-collagen protein-based `donut' scaffolds can support compartmentalized, 3D brain-like tissues over a year, without necrosis. This tissue model is highly innovative, supporting the differentiating neurons growth in a donut-shaped porous silk sponge within an optically cleared collagen-filled central region for axon connectivity and synapse formation, that will allow for the first time live in vivo studies (e.g., cell-based electrophysiology, trafficking, synaptic functionality) of an human AD brain-like tissue during ageing (months of cultivation) under controlled experimental conditions. More importantly, the architecture of the scaffolds was optimized to meet the metabolic demand of high-density cell cultures in terms of free diffusion of nutrients and oxygen, a fundamental requisite for long-term cultures and ageing-related studies. Thus, we propose to: 1) Assess AD- like phenotypes in FAD patient-derived 3D brain-like cultures; 2) Determine the extent to which the induction of aging in vitro accelerates the onset of AD-like phenotypes in FAD patient-derived 3D brain-like cultures.